U.S. patent number 4,171,358 [Application Number 05/677,951] was granted by the patent office on 1979-10-16 for novel contraceptive method.
This patent grant is currently assigned to Eli Lilly and Company. Invention is credited to Larry J. Black.
United States Patent |
4,171,358 |
Black |
October 16, 1979 |
Novel contraceptive method
Abstract
Progestational agents administered daily to female mammals
during the follicular phase only of the cycle prevents uterine
development associated with implantation in the luteal phase,
thereby preventing conception.
Inventors: |
Black; Larry J. (Indianapolis,
IN) |
Assignee: |
Eli Lilly and Company
(Indianapolis, IN)
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Family
ID: |
27040346 |
Appl.
No.: |
05/677,951 |
Filed: |
April 19, 1976 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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462458 |
Apr 19, 1974 |
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Current U.S.
Class: |
514/178;
514/843 |
Current CPC
Class: |
A61K
31/565 (20130101); A61K 31/57 (20130101); Y10S
514/843 (20130101) |
Current International
Class: |
A61K
31/565 (20060101); A61K 31/57 (20060101); A61K
031/56 () |
Field of
Search: |
;424/243 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Chemical Abstracts (1972), vol. 77, Pars. 10849..
|
Primary Examiner: Roberts; Elbert L.
Attorney, Agent or Firm: Rowe; James L. Smith; Everet F.
Parent Case Text
CROSS-REFERENCE
This application is a continuation-in-part of my copending
application Ser. No. 462,458 filed Apr. 19, 1974 now abandoned.
Claims
I claim:
1. A contraceptive method comprising the daily administration of a
progestin to a female mammal during the follicular phase of the
menstrual cycle at a dose insufficient to suppress ovulation in a
majority of female mammals and then administering no hormone during
the luteal phase of the menstrual cycle.
2. A process according to claim 1 in which the amount of progestin
administered to a human female is equivalent to an oral dosage of
300 to 500 mcg. of chlormadinone acetate per day.
3. A process according to claim 1 in which the dosage of progestin
administered is equivalent to an oral dosage of chlormadinone
acetate of from 5 to 8 mcg./kg. of female mammalian body weight per
day.
4. A contraceptive method for female humans comprising daily
administration of a progestin to a human female starting day 6 of
the menstrual cycle and continuing through day 16, day 1 of the
menstrual cycle being the day when the period commences, followed
by an absence of hormone administered during days 17-28 of the
menstrual cycle.
5. A process according to claim 4 in which amount of progestin
equivalent to a daily oral dose of 300 to 500 mg. of chlormadinone
acetate is administered per day to a human female during the 11-day
period.
Description
BACKGROUND OF THE INVENTION
The commonly used method of oral contraception in human females
consists of a combination of estrogen and progestin (progestational
agent) administered daily for 21 days. Menstruation occurs about 3
to 5 days after withdrawal and administration is reinitiated after
8 days, thereby beginning a new cycle. Inhibition of ovulation by
the progestin is believed to be the primary effect of this
contraceptive method. Rudel, et al., Fertility and Sterility, 16,
158-169, (1965) pointed out, however, that progestins, in addition
to their antiovulatory action, have other antifertility effects
including the production of a state of maturation of the
endometrium which is out of phase with ovulation, accompanied by
changes in the cervical mucus, these changes being incompatible
with vital and motile spermatozoa. The authors suggested that, in
an oral contraceptive agent comprising a combination of progestin
and estrogen, these other effects (in addition to inhibiting
ovulation) of progestins may be lost in the presence of added
estrogen. Martinez-manaoutou, et al., ibid, 17, 49-57 (1966) has
also suggested that a low dose of a progestin, specifically
chlormadinone acetate--a progestin without estrogenic
activity--prevented conception when administered continuously at
the rate of 0.5 mg. per day to human females during an entire
ovulatory cycle. It was determined that ovulation probably occurred
in 60 percent of the patients. Only one pregnancy occurred in 416
patients and 1600 menstrual cycles. From these observations, the
authors advocated the continuous administration of minimal doses of
a progestin as a contraceptive method in human females. The same
laboratory reported, ibid, 17, 57-62 (1967) that chlormadinone
acetate when administered to human females at a dosage of less than
500 mcg. daily demonstrated anti-estrogenic influence on the
cervical mucus without suppression of endometrial development. The
contraceptive effectiveness of the administered progestational
agent appeared to parallel closely the changes in the cervical
mucus. The same research group repeated in ibid, 18, 219-221 (1967)
their previous findings that a progestin given at dose levels which
do not inhibit ovulation is able to create a state of hormonal
imbalance as evidenced by a suppressed endometrium and/or a
thickened, scanty cervical mucus. The daily low level
administration of a progestin throughout the menstrual cycle was
the contraceptive method advocated by the authors for human
population control on a large scale, and they specifically
advocated the employment of an implanted pellet which would meter
out the progestin for a month or six weeks. The authors also
advocated the administration of estrogens after ovulation has
occurred in the hope that such administration would create another
hormonal imbalance hostile to conception and thus promote
contraception. In summary, this research group has found that the
low daily dosage of chlormadinone acetate (0.5 mg. daily), a
progestin without estrogenic activity, throughout the menstrual
cycle afforded a contraceptive method with an efficacy comparable
to the well-known marketed estrogen-progestin combinations.
Ufer, et al., U.S. Pat. No. 3,758,687 issued Sept. 11, 1973 covers
the administration to a female human at some point during the
interval from the 5th to the 8th day of the menstrual cycle of a
depot formulation of a progestin so as to prevent conception during
the remainder of the cycle and possibly for 2-3 cycles. The depot
formulation pays out the progestin continuously so that there is a
measureable amount present for at least one cycle and perhaps
longer. Kincl, U.S. Pat. No. 3,822,355 discloses the administration
of a progestational agent only during the luteal phase of the
menstrual cycle. Schmitt, et al. Chemical Abstracts, 77, 10849
(1972) disclose the continuous administration of a gestagen,
specifically chlormadinone, at low levels (minipills). The regimen
employed was a failure since half of the thirty-five women in the
test group showed bleeding disturbances. Rudel, U.S. Pat. No.
3,828,106, discloses an oral pharmaceutical form for administering
steroid hormones.
A relationship between the progestational state of the uterus and
implantation was reported originally by Corner and Allen, Am. J.
Physiol., 86, 74 (1928), 88, 340 (1929). The necessity of
pretreatment with the follicular hormone (estrogen) for optimal
response to the luteal hormone (progesterone) was later observed by
many others including Allen, Am. J. Physiol., 92, 612 (1930) and
Hisaw and Leonard, Am. J. Physiol., 92, 574 (1930). The phenomenon
of sequential influence of ovarian steroids is now widely accepted
by research workers studying mammalian reproductive cycles.
Estrogen priming is apparently not indispensable for a response to
a progestin, but the priming lowers the threshold for
progestational responses including progestational proliferation,
increased carbonic anhydrase, Pincus et al. Endocr., 61, 528
(1957), and synthesis of DNA and mitosis, Lee and Dukelow, J.
Reprod. Fert., 31 473 (1972). Rudel, et al., J. Reprod. Fert., 8,
305 (1964), observed that the progestational response to
chlormadinone acetate, a typical progestin, in humans is directly
related to the degree of estrogen stimulation of the endometrium at
the time treatment is started.
SUMMARY OF THE INVENTION
This invention provides a novel contraceptive method comprising the
daily administration of a progestin to a female mammal only during
the proliferative or follicular phase of the menstrual cycle with
no hormone being administered during the luteal phase. Customarily,
according to my novel contraceptive method, the progestin is first
administered to the cycling female mammal on the day following the
cessation of bleeding and administration of the progestin continues
on a daily basis during the first half, or the proliferative phase
of the cycle. Administration of the progestin is then discontinued
and no hormone, either estrogen or progestin is administered during
the second half, or luteal phase, of the cycle. With an average
human female, for example, this method of contraception would
involve self administration by the cycling female of a
progestational agent on a daily basis for the period beginning on
day 6 and continuing through day 16 of the cycle only with no
hormone or, alternatively, with a placebo being administered and
then stopping. The progestin dose level employed is that amount of
a progestin equivalent to 300-500 mcg. of chlormadinone acetate per
day for a human female or at the rate of about 5-8 mcg./kg./day of
female mammalian body weight for each day of the follicular phase.
As specified, the amount of progestational agent administered is
that amount which will give a progestational effect equivalent to
that given by the above dose levels of chlormadinone acetate. Other
progestational agents which can be employed in my novel
contraceptive process at dose levels giving an equivalent
progestational effect to that of 5-8 mcg. of chlormadinone
acetate/kg./day include progesterone (pregn-4-ene-3,20-dione),
norprogesterone (17.beta.-acetylestra-4-en-3-one), provera
(17-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione acetate),
norethindrone (17.alpha.-ethynyl-17.beta.-hydroyestr-4-en-3-one),
norgestrel
(dl-13.beta.-ethyl-17.alpha.-ethynyl-17.beta.-hydroxygon-4-en-3-one),
norethynodrel (17.alpha.-ethynylestr-4-en-3.beta.,17-diol
diacetate), 16.alpha.-chloroprogesterone
(16.alpha.-chloropregn-4-ene-3,20-dione),
6.alpha.-chloro-16.alpha.-methylprogesterone
(6.alpha.-chloro-16.alpha.-methylpregn-4-ene-3,20-dione),
chlormadinone (6-chloro pregna-4,6-dien-17.alpha.-ol-3,20-dione),
norethandrone (17.alpha.-ethyl-19-nortestosterone),
.DELTA.4,9-progesterone [19-nor-4,9(10)-pregnadiene-3,20-dione] and
the like. Dosages of these other progestational agents which are
equivalent to the above range of doses set forth for chlormadinone
acetate depend upon both the nature of the compound and the route
of administration. For example, norethandrolone is five times more
active than progesterone subcutaneously but fifty times more active
orally. Chlormadinone acetate is fifty times more active than
norethandrolone and five hundred times more active than
norethindrone by injection and fifty times more active than either
orally. Thus, a daily oral intake of chlormadinone acetate of from
300-500 mcg. per female would be equivalent to 15-25 mg. per female
per day of norethindrone. Similar equivalencies of other agents as
progestins to chlormadinone acetate can be determined
experimentally, and their dosage levels in my novel process can in
turn be determined from these data.
Unlike the regimen proposed by Ufer, U.S. Pat. No. 3,758,687,
wherein there is a single administration of a depot formulation
which continuously pays out the progestin into the blood stream for
a period equivalent to at least as long as one cycle, applicant
utilizes a daily dose regimen during the follicular phase only so
as to limit the progestational influence to the pre-ovulatory
phase.
While all progestational agents will prevent conception in female
mammals when administered at the rates set forth above, a preferred
group will be those classified as Type B progestational agents
according to the classification of Black and Kraay, J. Steroid.
Biochem., 4, 467 (1973). In general, these compounds will be
structurally related to the natural hormone, progesterone, which
has a .beta.-acetyl group at C.sub.17. While an hydroxy or acetoxyl
group may also be present at C.sub.17 in these compounds, these
oxygen functions will invariably have the .alpha.-orientation since
it is apparently the orientation of the 17-hydroxyl which decrees
whether a given progestin will be Type A or Type B according to the
criterion of Black and Kraay (loc. cit.).
Suppression of uterine responsiveness to progesterone is apparently
achieved through interference with the sensitizing effects of
estrogen. Administration of an estrogenic agent is less effective
due to its estrogenic contribution during the estrogen priming
phase.
The ability of progestational agents to affect the progestational
response by inhibiting fertility without inhibiting ovulation is
illustrated by the following experiment in which immature Dutch
Belted rabbits were primed with daily injections of 0.5 mcg. of
estradiol for six days followed by doses of 100 mcg. of
progesterone for five days. The group of progestins under test were
first administered at various dose levels only during the estrogen
priming phase to determine their effect upon the uterine response,
which was measured by sacrificing the rabbit, taking a 6 micron
section of each uterus, using both horns of individual animals,
mounting the tissue and then staining the tissue with
hematoxylin-eosin. The progestational responses were graded on a
scale of 0-4 according to the method of McPhail, J. Physiol., 83,
145 (1934). The mean response in 64 animals receiving only estrogen
in the estrogen-priming phase was 3.3. Table 1 below gives the
results of these determinations. In the table, column 1 gives the
name of the progestational agent administered during the
estrogen-priming phase, column 2, the number of animals used,
column 3, the dose of the progestational agent used for 6 days
against the standard dose of estrogen, specifically estradiol,
column 4, the uterine response graded on scale of from 0 to 4 as
previously set forth, and column 5, the standard error.
TABLE 1
__________________________________________________________________________
The Effect of Administration of Progestins in the Estrogen Priming
Phase No. of Dose/d .times. 6 -x Uterine Progestin Animals vs
E.sup.2 Response S.E.
__________________________________________________________________________
None 64 -- 3.3 0.1 Progesterone 6 1 mg 0.1 0.1 Progesterone 6 300
.mu.g 0.4 0.1 Progesterone 6 100 .mu.g 1.3 0.2 Progesterone 6 30
.mu.g 1.6 0.2 Norgestrel 6 100 .mu.g 0.5 0.1 Norgestrel 6 30 .mu.g
0.4 0.1 Norgestrel 6 10 .mu.g 2.2 0.2 Provera 6 300 .mu.g 0.3 0.1
Provera 6 100 .mu.g 0.2 0.1 Provera 6 30 .mu.g 0.1 0.1
Norprogesterone 6 300 .mu.g 0 -- Norprogesterone 6 100 .mu.g 0.2
0.1 Norprogesterone 6 30 .mu.g 0.6 0.1 6.alpha.-Chloro-16.alpha.- 6
1 mg 0.4 0.1 methyl pro- 5 300 .mu.g 0.4 0.1 gesterone 2 100 .mu.g
3.5 0.3 16.alpha.-Chloro- 6 3 mg 0.4 0.1 progesterone 6 1 mg 1.8
0.2 6 300 .mu.g 2.3 0.3 Nortestosterone 6 1 mg 2.4 0.3
Nortestosterone 6 300 .mu.g 2.7 0.1 Nortestosterone 6 100 .mu.g 3.3
0.1 Norethynodrel 6 1 mg 1.7 0.2 Norethynodrel 6 300 .mu.g 2.8 0.2
Norethynodrel 6 100 .mu.g 3.2 0.2 Norethindrone 6 300 .mu.g 0.2 0.1
Norethindrone 6 100 .mu.g 1.8 0.2 Norethindrone 6 30 .mu.g 1.8 0.1
Ethynodiol Diacetate 6 1 mg 0.7 0.1 Ethynodiol Diacetate 6 300
.mu.g 1.4 0.2 Ethynodiol Diacetate 5 100 .mu.g 1.5 0.2
Chloromadinone Acetate 12 100 .mu.g 0.3 0.1 Chloromadinone Acetate
6 30 .mu.g 0.2 0.1 Chloromadinone Acetate 11 10 .mu.g 0.2 0.1
Chloromadinone Acetate 9 3 .mu.g 1.8 0.2 .DELTA.4,9-Progesterone 3
1 mg 0 -- .DELTA.4,9-Progesterone 3 300 .mu.g 0.2 0.1
.DELTA.4,9-Progesterone 3 100 .mu.g 0 -- .DELTA.4,9-Progesterone 3
30 .mu.g 0.5 0.2
__________________________________________________________________________
In order to demonstrate that continued administration of progestins
through both the follicular and luteal phases of the menstrual
cycle is deleterious to the uterine effects of administered
progestin, a modification of the above experiment was carried out
in which the progestin was administered during both the estrogen
and progesterone administration phases of the cycle. Table 2 which
follows gives the result of these determinations in which the
uterine response was measured as before. In the table, column 1
gives the name of the progestin administered, column 2, the number
of animals used, column 3, the dosage of progestin administered
during the estrogen priming phase, column 4, the dosage of
progestin administered during the progesterone injection phase, and
columns 5 and 6, the uterine response measured as before, and the
standard error.
TABLE 2
__________________________________________________________________________
The Effect of Administration of Progestins in the Estrogen Priming
and Progestin Phases No. of Dose/d .times. 6 Dose/d .times. 5 -x
Uterine Progestin Animals vs E.sup.2 vs Prog. Response S.E.
__________________________________________________________________________
None 64 -- -- 3.3 0.1 Progesterone 6 300 .mu.g 300 g 2.7 0.1
Norgestrel 6 100 .mu.g 100 g 2.5 0.2 Provera 6 100 .mu.g 100 g 2.7
0.1 Norprogesterone 6 300 .mu.g 300 g 1.8 0.3
6.alpha.-Chloro-16.alpha. -- -- -- 3.5 0.3 methyl pro- 5 300 .mu.g
300 g 3.0 0.2 gesterone 16.alpha.-Chloro 6 3 mg 3 mg 3.5 0.3
progesterone Nortestosterone 6 1 mg 1 mg 2.3 0.3 Norethynodrel 5 1
mg 1 mg 2.1 0.3 Norethindrone 6 300 .mu.g 300 g 1.3 0.3 Ethynodiol
Di- 6 1 mg 1 mg 1.6 0.4 acetate Chloromadinone 12 100 .mu.g 100 g
2.4 0.2 Acetate
__________________________________________________________________________
As can be seen from Table 2, the continuation of administration of
the progestin during the progestational (luteal) phase of the cycle
tends to eliminate the suppression of uterine response seen when
the progestin is administered only during the estrogen (follicular)
phase of the cycle. In most instances in fact, the uterine response
is so close to the uterine response of the control animals (3.3)
that a progestin administered under these conditions does not
sufficiently suppress the uterine state to act reliably as an
antifertility or contraceptive agent and the possibility of
pregnancy would be encountered.
Progestins useful in the novel contraceptive process of this
invention can be administered to female mammals either orally or
parenterally. The orally active progestins, in general those
compounds which possess a 17.alpha.-acetoxy group, are conveniently
administered in the form of tablets or capsules. For administration
in these pharmaceutical forms, the compound is mixed with a
pharmaceutically-acceptable excipient and the mixture either loaded
into telescoping gelatin capsules or binders; lubricants and the
like are also added and the new mixture pressed into tablets. Each
tablet or capsule contains a dose of the progestin sufficient to
prevent conception when taken daily during the follicular phase.
With those progestins which are not orally active, as for example
progesterone itself, the compound is preferably administered
intramuscularly or intraperitoneally to the female mammal. This
parenteral mode of administration is preferred for those mammals
who are unable to take oral medication. In carrying out the novel
processes of this invention with human females, however, the oral
mode of administration is preferred. For such purposes, the
medication is placed in a dispenser containing a calendar on its
face and 21 or 28 pill slots. On a 21-day regimen, the first 10
slots are filled with progestin-containing tablets and the last 11
slots are filled with placebo tablets. With the 28-day dispenser,
the first 10 slots are filled with the progestin-containing tablets
and the last 18 slots are filled with placebo tablets. In either
case, the human female takes pill number 1 on day 1 which is the
first day after the cessation of bleeding from her last menstrual
period and continues till the dispenser is empty, starting with a
new dispenser on day 1 of her next cycle. An alternative mode of
administration would involve a dispenser with the first seven slots
filled with placebo tablets, then 10 slots filled with medication
followed by 11 slots again filled with placebo tablets. With this
dispenser, the human female would take the first placebo tablet on
the first day of menstruation.
* * * * *